SELECTIVE ACTIVATION OF CORTEX USING BENT MICRO-WIRES TO MAGNETICALLY STIMULATE NEURONS
Disclosed are micro-wire stimulators that magnetically stimulate nearby cells and/or their processes (e.g., nerve fiber, axons, dendrites, etc.). The micro-wire includes one or more bends. The micro-wire stimulator can facilitate the creation of stronger field gradients in one direction with much smaller gradients in orthogonal directions, allowing for selective targeting, or avoiding, of specific cell types within a targeted region. The bent micro-wire stimulator may be implanted into the cortex of the brain to selectively stimulate nearby neural cells having a particular orientation relative to the stimulator. A tip portion of the micro-wire may be rounded, or it may have corners forming other suitable geometric shapes.
This application is based on, claims priority to, and incorporates herein by reference in its entirety U.S. Provisional Application Ser. No. 62/311,609, filed Mar. 22, 2016, and entitled, “Micro-coil Implants for Selective Activation of Cortical Neurons.” The references cited in the above provisional patent application are also hereby incorporated by reference.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCHThis invention was made with government support under NIH/NEI R01 EY023651 and NIH/NINDS U01 NS099700 awarded by the National Institutes of Health and VA/RR&D RX001663 awarded by the Department of Veterans Affairs. The government has certain rights in the invention.
BACKGROUNDThe ability of electrical stimulation delivered from small micro-electrodes to modulate the activity of CNS neurons has opened up the possibility that implant arrays can be used to treat a wide range of neurological disorders. Notable successes include implantation of arrays of electrodes into the cochlea (cochlear prosthesis) to restore hearing to the profoundly deaf, and implantation of a single probe containing four distinct electrodes into the sub-thalamic nucleus, or other targets within the basal ganglia, to treat Parkinson's Disease or other disorders of the motor system. These successes have inspired much new effort over the last few decades to implant electrodes into many other regions of the central nervous system (CNS), including the neocortex, with the hope of treating many additional disorders. For example, arrays of microelectrodes have been implanted into the primary visual cortex with the goal of restoring vision to blind subjects. Encouragingly, subjects consistently report light percepts (phosphenes) in response to stimulation from a single electrode, and stimulation from an adjacent electrode elicits a phosphene in an adjacent region of visual space. Much additional effort has been devoted to stimulation of somatosensory cortex to provide somatosensory and proprioceptive feedback, e.g. as part of a brain-computer interface (BCI) in which cortical signals are “read” by the interface to allow the user to gain control of a prosthetic arm; the feedback signal is used to provide relevant feedback to the user, such as the force being exerted to grip a cup that is being lifted by the prosthetic arm. In addition to prosthetic-based applications, precise stimulation of the cortex has been and continues to be an essential component of many research studies that study fundamental questions of brain anatomy and/or physiology.
Unfortunately, the long-term viability of implantable cortical electrodes has been limited by the biological reactions that arise in response to implantation as well as by the fundamental biophysics of electric stimulation. For example, prolonged implantation alters the properties of the electrode, especially at the junction between the exposed metal and the surrounding insulation. Functionally, this changes the impedance of the electrode and thus the effectiveness with which stimulation is delivered. Another significant concern arises from the complex biological reactions induced by the implantation of any foreign material into cortex; activated astrocytes can encapsulate individual electrodes, forming a high-impedance barrier that can diminish the effectiveness of stimulation. It is likely that these types of changes contribute to reported difficulties in maintaining response consistency over time with implanted electrodes. For example, electrodes implanted into the primary visual cortex (V1) of macaque monkeys each reliably elicited a visual percept (phosphene) shortly after implantation, but individual electrodes lost effectiveness within a few months. Although larger groupings of electrodes could be used to generate phosphenes (e.g. 2×2 or 3×3), the need to couple electrodes together represents a significant loss in potential visual acuity. The use of non-penetrating approaches, such as electrodes positioned on the surface of the cortex, has been proposed to alleviate some of these concerns but unfortunately, surface stimulation requires considerably higher levels of current to induce an effect and further, cannot produce the same level of focal activation as implants, thereby greatly limiting their effectiveness.
Another important limitation associated with the implantation of electrodes into cortex is that the electric field induced by stimulation is spatially symmetric. The driving force for activation of a neuron subjected to artificial stimulation is proportional to either the strength of the electric field induced by the stimulating electrode along its length or to the gradient of the induced field, i.e. a rapidly changing field along the length of an axon is highly effective in many situations. Referring to
Magnetic stimulation is an attractive alternative to electrical stimulation from implanted electrodes. This is because direct contact between the metal coils and the targeted neural tissue is not necessary and thus the stability of the interface is much less likely to deteriorate over time. Further, because magnetic fields pass readily through biological materials, they are not significantly diminished by even the most severe encapsulation, further enhancing the stability of coil performance over time. Note that while magnetic fields are not thought to directly modulate neuronal activity, the electric fields they induce are effective; thus, the electric field induced by the coil can be ‘carried’ beyond the region of encapsulation to drive activation. Coils small enough to be safely implanted into cortex were not thought to be sufficiently powerful to induce neural activation but recent studies have shown that small-sized inductors (coils) (0.5 mm width×1.0 mm length) could indeed modulate neuronal activity. While attractive, their size was still too large to safely implant into cortex, especially if such coils were to be part of a multi-coil array used to simultaneously modulate activity in multiple nearby regions. This is especially problematic because the orientation of the coil that best activates vertically-oriented pyramidal neurons necessitates the coil to be oriented in the horizontal direction, thereby increasing the cross-sectional area of the implant. Thus, it would be desirable to have a magnetic stimulator that is small enough to be safely implanted into cortex but still effective at providing selective stimulation and maintaining consistency over time.
SUMMARY OF THE PRESENT DISCLOSUREDisclosed are exemplary systems and methods involving micro-wire stimulators capable of magnetically stimulating nearby cells. The design utilizes one or more bends in the micro-wire to enhance the strength of the induced field. In addition, precise arrangements of the bends can facilitate the creation of stronger field gradients in one direction with much smaller gradients in orthogonal directions, thus allowing for selective targeting, or avoiding, of specific cell types within a targeted region. In exemplary versions, a micro-wire stimulator may be implanted into the cortex of the brain to selectively stimulate nearby neural cells having a particular orientation relative to the stimulator. The micro-wire design results in a reduced cross-sectional surface area of the micro-wire stimulator; the smaller area helps to minimize both the trauma arising from implantation as well as the level of biological response that arises over time. Further advantages and features of the invention will be apparent from the remainder of this document in conjunction with the associated drawings.
The foregoing and other aspects and advantages of the invention will appear from the following description. In the description, reference is made to the accompanying drawings that form a part hereof, and in which there is shown by way of illustration preferred versions of the invention. Such versions do not necessarily represent the full scope of the invention, however, and reference is made therefore to the claims and herein for interpreting the scope of the invention. It is noted that components shown in the figures are not necessarily to scale.
DETAILED DESCRIPTION OF THE PRESENT DISCLOSUREMagnetic stimulation offers several potential advantages over conventional electrode-based stimulation. For example, referring to
Exemplary stimulators that are small enough to be safely implanted, and yet capable of generating electric fields large enough for neuronal activation, may include insulated and bent micro-wires with, for example, one of the configurations shown in
The exemplary stimulator 210 includes micro-wire 212 bent to form a more pointed tip portion 216, and stimulator 220 includes micro-wire 222 bent to form a “W” shape at tip portion 226. Micro-wires 212 and 222 include insulation 214, 224, respectively. Because electric fields for neuronal activation are magnetically induced and not generated through direct contact with a conductor, the stimulators may be insulated with a biologically inert material (e.g. polyimide, parylene-C, SU-8, polytetrafluoroethylene (PTFE), polycarbonate (PC), and Liquid Crystal Polymer (LCP)) that can help to reduce the reactions that can occur between the stimulator and biological tissue, extending the life of the stimulators and further minimizing the possibility of adverse effects in the tissue or other complications. Referring to
Computational modeling can be used to estimate the size of the magnetic field induced by exemplary configurations, as well as the resulting electric fields and their spatial gradients in 3 different orthogonal orientations.
As illustrated, changes to the shape of the bent wire can have a significant impact on the relative strengths of the horizontal and vertical gradients, and consequently, different stimulator designs can be used to create different activation profiles. For example, changes to the length, separation, sharpness as well as the number of the individual bends could be used to further modulate the asymmetry between the induced fields that arise along different orientations. In addition, other designs can be used to selectively target other types of cortical neurons (or other cells). For example, basket cells and chandelier cells (i.e., inhibitory interneurons) in the cortex have axons that extend horizontally; in cases where it is desirable to target such types of neurons, the metal wires can be designed to have a straight portion along the horizontal axis and a zigzag (repeating “W” shapes) 280 portion along the vertical axis. A “conical” shape with an elongated bottom (such as in 270) may also be used. As shown, the elongated bottom of 270 is linear, but need not be so; alternatively, the elongated bottom may be, for example, W-shaped, zig-zagged, helical, etc. (as can other linear segments of the exemplary micro-wires that are shown in the figures). In other configurations, the elongated bottom may be slanted at an angle Θ (such as in 290) with respect to a long axis of the micro-wire (or with respect to an axis orthogonal to the long axis of the micro-wire) so as to target or avoid neurons or interneurons at various different angles with respect to the micro-wire stimulator. Similarly, the elongated bottom of 290 also need not be linear but can have other shapes deemed suitable.
It is further noted that the strongest part of the gradient typically corresponds to the parts of the wires with the sharpest bends. This allows specific cortical depths to be targeted using different shapes. Thus, for example, pyramidal neurons associated with Layer 2/3 can be driven independently of the pyramidal neurons associated with Layer 5. Additionally, as will be further discussed, different cortical layers can be targeted with, for example, penetrating probes of different lengths (
Fabricated micro-wires were first tested for their ability to activate cortical neurons during in vitro experiments using coronal brain slices from mice (
To explore the ability of the exemplary micro-wires to selectively target neurons, experiments were run in which the orientation of the micro-wire was varied relative to the orientation of the targeted PN (
Referring to
For direct activation, thresholds were generally lowest when the tip of the micro-wire was situated over the proximal axon at a distance of about 50 μm from the soma. For indirect activation, thresholds were generally lowest when the micro-wire was over the apical dendrite 805 at a distance of about 200 μm from the soma 820. It is noted that for the responses that arose through indirect activation (
To test the effectiveness of certain implementations of micro-fabricated bent-wire stimulators for cortical activation, the stimulator shape depicted in
The exemplary designs in
Referring to the exemplary stimulator probe 600 in
In the cross-sectional view of
In alternative versions, stimulator 600 may include “layers” of micro-wires “stacked” on top of each other. For example, referring to the cross-sectional view of an exemplary stimulator in
To verify activation of cortical neurons, the bent-wire stimulator 700 of
Referring to
Referring to
Referring to
It is noted that a “bend” in the exemplary micro-wires discussed above refers to a change in direction in the micro-wire. The bend may be sharp (forming a corner where two segments intersects at an angle), but need not be so. As disclosed above, the change in direction may a rounded intersection of segments meeting where the direction is changed. It is also noted that the approach discussed above may be adapted for activation of any electrically active cells, including neurons outside the cortex, including peripheral axons as well as muscle cells. It is moreover noted that use of the term “micro” in “micro-wire” is not intended to limit the range of sizes (widths, diameters, lengths) that could be used in exemplary wires.
Further, although conventional coil-based inductors could potentially generate magnetic fields that achieve selective neuronal activation, the cross-sectional profile of even the smallest such inductors (500 μm in diameter and 1 mm long) are nearly 100 times that of commonly used electrode implants, and cannot be safely implanted into the cortex. Also, existing micro-coil inductors require thresholds of 717 mA for activation, whereas the thresholds for in vitro activation with exemplary versions of the micro-wire discussed above were 44.21 mA (about 16 times smaller). The lower threshold levels that were observed here likely arose because the smaller size of the micro-wires not only generated stronger fields but also allowed for closer proximity to targeted neurons. It is noted that the magnitude of the gradients from the exemplary micro-fabricated bent-wire stimulators are comparable in magnitude to the gradients that would result using larger (and impractical) conventional coil inductors, and can be expected to be similarly effective in activating neural cells.
Referring to
Modeling of bent-wire stimulators: To calculate or model the spatial gradient of induced electric fields (E-fields) arising from the flow of current through differently-shaped exemplary micro-wires, some or all of the following relationships may be applicable.
From Faraday's Laws, the E-field, {right arrow over (E)}, is related to the time varying magnetic field by:
Because the magnetic field, {right arrow over (B)}, can be obtained by taking the curl of the magnetic vector potential, {right arrow over (A)}, (i.e. {right arrow over (B)}=∇×{right arrow over (A)}) the equation for E-field can be expressed as:
Under the assumptions that there is no charge on the micro-wire and the current distribution in the micro-wire is uniform (that is, quasi-static condition), ∇V is equal to 0 and Eqn. 2 becomes:
The magnetic vector potential is calculated from the micro-wire geometry as follows:
where μ0 is the permeability constant, N is the number of turns, i is the electric current through the micro-wire, R is the vector between the micro-wire segment and the target segment at which the E-field is calculated, and dl is the small segment of the micro-wire.
If the principal axis of the pyramidal neurons (PNs) within each cortical column is approximately parallel to the x-axis, the E-field along the cortical column can be calculated by numerically integrating along the length of the micro-wire loop.
where the x-dimension corresponds to the long axis of the PN.
Integrating the ∂{right arrow over (E)}x with respect to the x component of the line gives the following equation for {right arrow over (E)}x.
In Eqn. 6, the micro-wire element lies at (x0,y0,z0) and the E-field is calculated at (x,y,z). The x1 and the x2 represent the positions of the corners of the rectangular micro-wire in the x-axis. The spatial gradient,
is calculated by taking the derivative of the analytical solution for {right arrow over (E)}x from Eqn. 6. The input current to the micro-wire, i, was a half period of 3 kHz sinusoidal waveform with an amplitude of 1 mA.
Fabrication and testing of exemplary bent-wire stimulators: An exemplary fabrication process is based on silicon processing techniques. First, a 50 μm thick 4-inch silicon wafer may be bonded to a handling wafer with an adhesive. Subsequently, a 100-200 nm SiO2 layer may be deposited using plasma-enhanced chemical vapor deposition (PECVD). Then a 2 μm thick copper layer may be sputtered using electron beam (e-beam) assisted physical vapor deposition (PVD) with a 10 nm thin titanium layer to improve adhesion. Next, a photoresist, used as mask for the next etching step, may be spin-coated and baked. The photoresist can be patterned by exposure to UV light through a phase-shifting photomask. After that, the copper may be wet-etched using a solution of Transene Copper Etch 49-1. The photoresist can be stripped off in acetone and then 300 nm insulating SiO2 may be deposited on top using PECVD. The area of the electrical contact pads may be shadowed to help ensure it is free of the top insulation. Following this step, a photoresist, used as the mask in the silicon etch, may be spin-coated and patterned. The 50 μm thick silicon substrate may be etched through using deep reactive ion etching (DRIE). The resulting bent-wire structures are then released from the handling wafer in acetone and dried. A bent-wire structure may also be made using, for example, an ultra-fine copper wire (50 μm bare diameter (45-AWG), Polyurethane base coat, Polyamide overcoat, 60 μm with insulation, Essex, Fort Wayne, Ind., USA).
In other implementations, the fabricated bent-wires were assembled with copper wire leads (34-AWG, polyurethane inner coat and nylon over coat) (Belden, Richmond, Ind., USA). The electrical contacts of micro-wires were connected to the copper wire leads using a silver conductive epoxy (CircuitWorks Conductive Epoxy, ITW Chemtronics, Kennesaw, Ga., USA). Assembled micro-wires were mounted on a custom-made plastic holder with an instant adhesive and the distal ends of the copper wire leads were attached to the signal and ground leads of a BNC connector. The custom-made assemblies were secured to the micromanipulator of a stereotaxic frame (Model 900, David Kopf instruments, Tujunga, Calif., USA) for accurate positioning over mouse cortex.
Each micro-wire assembly was tested both before and after each experiment to ensure that there was no leakage of electrical current from the micro-wire into the mouse cortex. Micro-wires were submerged in physiological solution (0.9% NaCl) and the impedance between one of the micro-wire terminals and an electrode immersed in the physiological solution was measured before and after each in vivo animal experiment. Impedances above 200 MΩ were considered indicative of adequate insulation. The high impedance ensured that direct electrical currents did not contribute to any of the elicited neural activity underlying observed mouse behaviors.
Micro-magnetic stimulation drive: In certain implementations, the output of a function generator (AFG3021B, Tektronix Inc., Beaverton, Oreg.) was connected to a 1,000 W audio amplifier (PB717X, Pyramid Inc., Brooklyn, N.Y.) with a gain of 5.6 V/V and a bandwidth of 70 kHz. The audio amplifier was powered by a battery (LC-R1233P, Panasonic Corp., Newark, N.J.). The output of the amplifier was monitored with an oscilloscope (TDS2014C, Tektronix Inc., Beaverton, Oreg.). Stimulation pulses may consist of a single full period 3 kHz sinusoid waveform. The amplitude of sinusoids from the function generator ranged from 0-200 mV. The output of the amplifier for sinusoids was 0-1.12 V. Single burst stimulation consisting of 5 pulses or 10 pulses was delivered at 10 Hz and 100 Hz, respectively. Repetitive stimulation at 1 pulse per second was delivered for a total of 10 seconds. Other repetitive stimulations consisted of 3 pulses per second at 10, 50, or 100 Hz for a total duration of 5 seconds.
The present disclosure has described one or more preferred embodiments, and it should be appreciated that many equivalents, alternatives, variations, and modifications, aside from those expressly stated, are possible and within the scope of the invention.
Claims
1. A method for stimulating cells and/or their processes in a subject, the method comprising:
- positioning a micro-wire proximal to the cells to be stimulated, the micro-wire having one or more bends; and
- providing an electrical input to the micro-wire to generate a magnetic field which will induce an electric field in the subject;
- wherein the cells are selectively activated cells based on orientation relative to the micro-wire.
2. The method of claim 1, wherein the micro-wire is insulated with a biologically inert dielectric.
3. The method of claim 1, wherein the cells include at least one of:
- neurons;
- neurons, axons, and/or dendrites in the cortex;
- neurons, axons, and/or dendrites in the deep brain;
- neurons, axons, and/or dendrites in the basal ganglia;
- neurons, axons, and/or dendrites in the spinal cord; or
- neurons, axons, and/or dendrites of peripheral nerves.
4-8. (canceled)
9. The method of claim 3, wherein the micro-wire is positioned in the cortex of the subject.
10. The method of claim 9, wherein the micro-wire is one micro-wire in an array of micro-wires, and wherein the array of micro-wires is positioned in the visual cortex of the subject to generate visual percepts.
11. The method of claim 9, wherein the micro-wire is positioned in at least one of:
- a motor cortex of the subject;
- a somatosensory cortex of the subject; or
- a motor cortex and a somatosensory cortex of the subject.
12-13. (canceled)
14. The method of claim 9, wherein at least one of the following:
- neurons aligned substantially orthogonal to a surface of the cortex are preferentially activated;
- neurons aligned substantially parallel to a surface of the cortex are preferentially activated;
- neurons aligned substantially parallel to a surface of the cortex are preferentially not activated; or
- neurons aligned substantially orthogonal to a surface of the cortex are preferentially not activated.
15-17. (canceled)
18. The method of claim 1, wherein the micro-wire includes a tip portion that is at least one of triangular, trapezoidal, W-shaped, partly zig-zagged, or partly conical.
19-22. (canceled)
23. The method of claim 1, wherein the micro-wire includes a tip portion terminating in an elongated portion that is perpendicular to a long axis of the micro-wire.
24. The method of claim 1, wherein the micro-wire includes a tip portion terminating in a substantially elongated portion that is angled at an angle Θ with respect to a long axis of the micro-wire.
25. The method of claim 1, wherein the micro-wire includes at least one of a tip portion that is rounded or a conductor formed on a substrate.
26. (canceled)
27. The method of claim 1, wherein the micro-wire is part of a probe which includes a set of micro-wires.
28. The method of claim 27, wherein two micro-wires are connected such that a current travels through a loop formed by the two connected micro-wires.
29. The method of claim 27, wherein the probe includes at least two micro-wires with different lengths.
30. The method of claim 29, wherein the cells are neurons in the cortex of the brain of the subject, and wherein the method further comprises activating one or more neurons in a shallower layer of the cortex using a relatively short micro-wire, and activating one or more neurons in a deeper layer of the cortex using a relatively longer micro-wire.
31. The method of claim 29, wherein stimulation is independently applied at multiple depths.
32. A system for stimulating a cortex of a subject, the system comprising:
- a set of micro-wires, each micro-wire having one or more bends formed therein; and
- a generator coupled to the set of micro-wires to provide an electrical input thereto;
- wherein the micro-wires are configured to receive an electrical input that generates a magnetic field that preferentially excites neurons based on orientation relative to the orientation of the micro-wires.
33. The system of claim 32, wherein vertically oriented pyramidal neurons (PNs) are activated preferentially over horizontally-oriented passing axons.
34. The system of claim 32, further including a telemetry unit for receiving data or power.
35. The system of claim 32, wherein the system forms at least one of a visual cortex implant and a motor cortex implant.
36. (canceled)
37. A device for stimulating a cortex of a subject, the device comprising an insulated micro-wire having one or more bends formed therein, the micro-wire being configured to receive an electrical input that generates a magnetic field to induce a spatially asymmetrical electric field.
Type: Application
Filed: Mar 22, 2017
Publication Date: Apr 4, 2019
Patent Grant number: 11007372
Inventors: Seungwoo Lee (Boston, MA), Shelley Fried (Boston, MA)
Application Number: 16/086,584